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PMID: 19119233 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Regulation of neuronal survival factor MEF2D by chaperone-mediated autophagy.

Science (New York, N.Y.) ·Vol. 323 ·No. 5910 ·2009-01-02 ·Pages 124-7

Yang Q, She H, Gearing M, Colla E, Lee M, Shacka JJ, Mao Z

Abstract

Chaperone-mediated autophagy controls the degradation of selective cytosolic proteins and may protect neurons against degeneration. In a neuronal cell line, we found that chaperone-mediated autophagy regulated the activity of myocyte enhancer factor 2D (MEF2D), a transcription factor required for neuronal survival. MEF2D was observed to continuously shuttle to the cytoplasm, interact with the chaperone Hsc70, and undergo degradation. Inhibition of chaperone-mediated autophagy caused accumulation of inactive MEF2D in the cytoplasm. MEF2D levels were increased in the brains of alpha-synuclein transgenic mice and patients with Parkinson's disease. Wild-type alpha-synuclein and a Parkinson's disease-associated mutant disrupted the MEF2D-Hsc70 binding and led to neuronal death. Thus, chaperone-mediated autophagy modulates the neuronal survival machinery, and dysregulation of this pathway is associated with Parkinson's disease.

MeSH Terms
Amino Acid Motifs Ammonium Chloride/pharmacology Animals Autophagy Brain/metabolism Cell Line Cell Nucleus/metabolism Cell Survival Cytoplasm/metabolism DNA/metabolism HSC70 Heat-Shock Proteins/metabolism Lysosomal-Associated Membrane Protein 2/metabolism Lysosomes/metabolism MADS Domain Proteins/metabolism MEF2 Transcription Factors Mice Mice, Transgenic Molecular Chaperones/metabolism Myogenic Regulatory Factors/chemistry,metabolism Neurons/cytology,metabolism Parkinson Disease/metabolism Protein Binding Protein Transport Rats Rats, Long-Evans alpha-Synuclein/genetics,metabolism
Chemicals
HSC70 Heat-Shock Proteins Hspa8 protein, mouse Lysosomal-Associated Membrane Protein 2 MADS Domain Proteins MEF2 Transcription Factors MEF2D protein, human Mef2d protein, mouse Molecular Chaperones Myogenic Regulatory Factors alpha-Synuclein Ammonium Chloride DNA
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Yang Qian
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
She Hua
Gearing Marla
Colla Emanuela
Lee Michael
Shacka John J
Mao Zixu
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.1166088
Published
2009-01-02
Pages
124-7
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC2666000
Subset
IM
Grants
NINDS NIH HHS · NS048254 · United States
NINDS NIH HHS · NS038065 · United States
NIA NIH HHS · R01 AG023695-05 · United States
NIA NIH HHS · R01 AG023695-04 · United States
NIA NIH HHS · R01 AG023695-03 · United States
NINDS NIH HHS · P30 NS055077 · United States
NINDS NIH HHS · NS055077 · United States
NINDS NIH HHS · R01 NS048254-02 · United States
NIA NIH HHS · R01 AG023695 · United States
NINDS NIH HHS · R01 NS048254-06 · United States
NINDS NIH HHS · P30 NS055077-01A2 · United States
NIA NIH HHS · R01 AG023695-02 · United States
NINDS NIH HHS · R01 NS048254-03 · United States
NIA NIH HHS · P50 AG025688-03 · United States
NINDS NIH HHS · NS57098 · United States
NIA NIH HHS · P50 AG025688 · United States
NINDS NIH HHS · R01 NS048254-04 · United States
NINDS NIH HHS · NS47466 · United States
NIA NIH HHS · AG023695 · United States
NINDS NIH HHS · R01 NS048254-05 · United States
NINDS NIH HHS · R01 NS048254 · United States
External Links
PubMed source DOI: 10.1126/science.1166088 PMC Full Text View journal details
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